Correlation between cognitive phenotype, neural morphology and molecular alterations in mouse models of Williams-Beuren syndrome : new therapeutic approaches

Borralleras Fumaña, Cristina

Correlation between cognitive phenotype, neural morphology and molecular alterations in mouse models of Williams-Beuren syndrome : new therapeutic approaches

Document Type

Doctoral thesis
Published Version

Author

Borralleras Fumaña, Cristina

Director

Campuzano Uceda, María Victoria
Pérez Jurado, Luis Alberto

Publication Date

2016-07-15

Pages

239 p.

License

Citation

Borralleras Fumaña, C. Correlation between cognitive phenotype, neural morphology and molecular alterations in mouse models of Williams-Beuren syndrome : new therapeutic approaches. Universitat Pompeu Fabra; 2016. handle: http://hdl.handle.net/10803/388032

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of 26-28 contiguous genes in the 7q11.23 region. So far, a great deal of attention has been focused on its unique and distinctive neurocognitive profile. Although important progress has been made with regards to clinical characterization or genotype-phenotype correlations, a much deeper insight into the neuropathological features of WBS would be of great interest. In this thesis project, we have used a WBS mouse model carrying a heterozygous deletion that mimics the most common deletion found in patients. We have characterized the cognitive and behavioral phenotype of these mice and we have indentified molecular and neuroanatomical alterations relevant for the disease. Moreover, we have attempted two novel therapeutic strategies: a gene therapy and a pharmacological approach. The results obtained highlight the utility of this animal model to study the mechanisms underlying the disease as well as to evaluate novel therapeutic strategies.
La síndrome de Williams-Beuren (SWB) és una malaltia rara del neurodesenvolupament causada per una deleció heterozigota d’entre 26 i 28 gens contigus a la regió 7q11.23. Fins ara, una gran part de l’atenció s’ha centrat en el seu característic perfil neurocognitiu. Tot i que s’han fet progressos molt importants pel que fa a la caracterització clínica o a les correlacions genotip-fenotip, seria de gran interès aprofundir en les característiques neuropatològiques de la SWB. En aquesta tesi, hem utilitzat un model de ratolí del SWB amb una deleció heterozigota que mimetitza la deleció més comuna d’aquests pacients. Hem caracteritzat el fenotip cognitiu i comportamental d’aquests ratolins i hem identificat alteracions moleculars i neuroanatòmiques rellevants per a la malaltia. Per altra banda, hem dut a terme dues estratègies terapèutiques: una teràpia gènica i un tractament farmacològic. Els resultats obtinguts remarquen la utilitat d’aquest model animal per a l’estudi dels mecanismes subjacents a la malaltia així com també per a avaluar noves aproximacions terapèutiques.

Keywords

Williams-Beuren syndrome, Mouse models, Neurocognitive phenotype, General transcription factor II-I (Gtf2i), Synaptic plasticity, Síndrome de Williams-Beuren, Models de ratolí, Plasticitat sinàptica